TP53 Mutations and Phosphatidylinositol 3-Kinase/AKT Pathway Alterations Are Key Determinants of Breast Cancer Outcome Independent of Subtype and Stage

PURPOSE Breast cancer (BC) is a heterogeneous disease with genetic alterations influencing prognosis and treatment response. TP53 mutations ( TP53 muts) are present in approximately 30% of BC, but their prognostic impact remains controversial. In addition, the phosphatidylinositol 3-kinase (PI3K)/Ak strain transforming (AKT) pathway is frequently altered and represents a promising therapeutic target for BC. Understanding the combined prognostic impact of TP53 mut and PI3K/AKT pathway alterations across BC subtypes remains underexplored. METHODS This retrospective cohort study integrated clinical and genomic data from 4,265 patients with BC from the Molecular Taxonomy of Breast Cancer International Consortium (n = 2,509) and the Memorial Sloan Kettering Cancer Center (n = 1,756). Genetic profiling identified TP53 mut and PI3K/AKT pathway alterations ( AKT1 , AKT2 , AKT3 , PIK3CA , PTEN , RICTOR ). Survival outcomes were assessed using Kaplan-Meier survival analysis and multivariable Cox proportional hazards models. RESULTS In 3,807 patients with available gene alteration status, TP53 mut was associated with younger age, higher tumor grade, advanced stage, and aggressive subtypes ( P < .001). TP53 mut was associated with worse survival independent of subtype, stage, age, and grade (hazard ratio HR, 1.43 95% CI, 1.24 to 1.66; P < .0001). The type of TP53 mut has also been found to be prognostic in BC. PI3K/AKT pathway alterations were more frequent in TP53 mut tumors and independently associated with worse survival (HR, 1.18 95% CI, 1.03 to 1.35; P = .0173). The combined presence of TP53 mut and PI3K/AKT alterations resulted in the worst survival outcomes (HR, 1.61 95% CI, 1.32 to 1.97; P < .0001). CONCLUSION TP53 mut status is a critical prognostic factor in BC, independent of subtypes and stage, and its adverse impact is amplified by PI3K/AKT pathway alterations. These findings emphasize the integration of genetic profiling into routine clinical practice to refine treatment strategies and identify potential therapeutic targets for this high-risk population.